Synthesis and cardiac electrophysiological activity of aryl-substituted derivatives of the class III antiarrhythmic agent sematilide. Potential class I/III agents.
Twelve novel derivatives of the selective class III antiarrhythmic agent sematilide were prepared in an attempt to incorporate both class I and class III electrophysiological properties into a single molecule. Electrophysiological activity was determined by standard microelectrode techniques in canine cardiac Purkinje fibers. Initial assessment of class I efficacy was carried out in a ouabain-induced arrhythmia model in guinea pigs. All of the compounds prolonged action potential duration in Purkinje fibers (class III activity), and three were active against ouabain-induced arrhythmias (class I activity). Selected compounds were evaluated further in dogs for efficacy against arrhythmias occurring 24 h following coronary ligation (automatic arrhythmias) and induced by using programmed electrical stimulation techniques (reentrant arrhythmias). The most effective compounds from the series are 3g and -j, which were effective in both canine models. Molecular modeling and structure-activity relationships are discussed.
Phillips
G B
GB
Department of Medicinal Chemistry, Berlex Laboratories, Inc., Cedar Knolls, New Jersey 07927.
Morgan
T K
TK
Nickisch
K
K
Lind
J M
JM
Gomez
R P
RP
Wohl
R A
RA
Argentieri
T M
TM
Sullivan
M E
ME
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000138:chemical synthesis* / Q000145:classification / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000188:drug therapy*; D055598:Chemical Phenomena; D002621:Chemistry; D004285:Dogs; D015195:Drug Design; D004594:Electrophysiology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D010042:Ouabain; D011342:Procainamide / Q000031:analogs & derivatives*; D011690:Purkinje Fibers; D013329:Structure-Activity Relationship
D000889:Anti-Arrhythmia Agents; C062818:sematilide; D010042:Ouabain; D011342:Procainamide